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Title: Functional characterisation of the genes mutated in dyskeratosis congenita
Author: Beswick, Richard William
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2013
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Dyskeratosis congenita (DC) is a multi system disorder that exhibits considerable clinical and genetic heterogeneity. It is characterised by mucocutaneous features, bone marrow failure and a predisposition to cancer. Research has identified mutations affecting several telomerase components and patients often have short telomeres, implicating defective telomere maintenance in this disease. Affected components include dyskerin, NOP10 and NHP2, which together with GAR1 form a protein core common to telomerase and all other H/ACA ribonucleoprotein complexes (H/ACA RNPs). Initially characterised as H/ACA RNP components important for pseudouridylation and rRNA processing, their role in the functionally distinct telomerase complex and telomere maintenance is less defined. In order to better understand their implications in DC, this study investigated the importance of these core proteins for the integrity and function of telomerase in human cells. RNAi knockdown studies demonstrated that dyskerin, NOP10 and NHP2 are necessary for the accumulation of TERC (telomerase RNA component); dyskerin and NOP10 for telomerase activity. Moreover, dyskerin was found to be important for maintaining telomere length over time. The impact of NOP10 and NHP2 missense mutations was also analysed in vitro, which indicated that they impair TERC accumulation. The potential effect on pseudouridylation was also considered in this study; the analysis of other H/ACA RNA levels in these knockdown experiments and in a cohort of patients with DKC1 mutations revealed an irregular and inconsistent impact compared to that observed on TERC. Finally, defective telomere maintenance is heavily implicated as the primary cause of DC and very short telomeres have been proposed as a diagnostic marker. This study investigated telomere length in a patient cohort of unprecedented size. It demonstrated the prevalence of the telomere length defect, but telomere length was not found to correlate with either genetic subtype or disease severity, implicating the rate of telomere shortening as the correlating factor instead.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine ; Paediatrics ; Dyskeratosis congenita ; Congenital diseases